Neuroglia in neurodegeneration

doi:10.1016/j.brainresrev.2009.11.004

Brain Research Reviews

Volume 63, Issues 1–2, May 2010, Pages 189-211

https://doi.org/10.1016/j.brainresrev.2009.11.004 Get rights and content

Abstract

Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity within brain circuits affecting neuronal–neuronal, neuronal–glial and glial–glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.

Section snippets

Neuroglia—the concept

The complexity of the cellular circuitry of human brain is unparalleled by any other living system known so far. The neural cells are exceedingly densely packed within a strictly limited volume of the skull, thus requiring a specific attention to the control of brain homeostasis throughout early development and postnatal functioning. This specific requirement is manifested in the highly developed brain–blood barrier, which essentially limits the impact of bodily homeostatic systems on the

Astrocytes organise the brain matter

The astrocytes provide for the micro-architecture of the grey matter by dividing it (through the process known as “tiling” (Bushong et al., 2004)) into relatively independent structural units. Each protoplasmic astrocyte dwelling in the grey matter establishes its own territory within the limits of its elaborated arbour of processes; this domain organisation exists in both rodents and humans (Bushong et al., 2002, Nedergaard et al., 2003, Oberheim et al., 2009, Wilhelmsson et al., 2006). Within

Neuroglia determines the outcome of neurological pathology

Glial cells are fundamental for the control of brain homeostasis, and they represent the intrinsic brain defence system. First, the homeostatic systems expressed in astrocytes prevent homeostatic imbalances triggered by various types of stressors applied to CNS. Second, two types of glia—the astrocytes and microglia—possess evolutionary conserved programs of activation in response to brain damage. A variety of brain insults trigger a condition generally referred to as reactive gliosis, which

Astrocytes in neurodegeneration and AD

The causes of neurodegenerative diseases are many, from traumatic or infectious attacks to intrinsic processes associated with genetic predispositions or the accumulation of sporadic errors of yet unknown origins. The neurodegenerative disorders, which affect the main human asset, the intellect, are in essence the failures of connectivity within brain circuitry. The astrocytes, being involved in synaptic birth, maturation and maintenance, as well as in controlling the brain homeostasis and

Amyotrophic lateral sclerosis

The primary pathological feature of ALS is the loss of motor neurones (Talbot, 2002), which is accompanied by a robust glial response including the activation of microglia and astrocytes as well as the expression of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) in the spinal cord (Almer et al., 1999, Barbeito et al., 2004, Phul et al., 2000, Yasojima et al., 2001). The histological studies of post-mortem brains and spinal cord tissue were recently supported by a study using the PET

Concluding remarks

The neurodegenerative diseases result from the failure in brain connectivity, which is formed by neuronal–neuronal, neuronal–glial and glial–glial contacts. Contrary to past beliefs, which regarded neuropathology to be solely associated with neuronal malfunction and neuronal cell death, the new doctrine, which regards glia as a central element in neurological diseases is emerging. The neurodegeneration is driven by complex astroglial reactions which include astroglial atrophy with a subsequent

Acknowledgments

Authors research was supported by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe (10-6789) and the Wilhelm Sander foundation (2006.001.1) grants to MTH; Alzheimer's Research Trust (UK) Programme Grant (ART/PG2004A/1) to AV and JJR; National Institute of Health (NIH) grant to AV, Grant Agency of the Czech Republic (GACR 309/09/1696) to JJR and (GACR 305/08/1384) to AV.

References (319)

AbbracchioM.P. et al.
Purinergic signalling in the nervous system: an overview
Trends Neurosci.
(2009)
AgulhonC. et al.
What is the role of astrocyte calcium in neurophysiology?
Neuron
(2008)
AkiyamaH. et al.
Inflammation and Alzheimer's disease
Neurobiol. Aging
(2000)
AnguloM.C. et al.
GABA, a forgotten gliotransmitter
Prog. Neurobiol.
(2008)
AraqueA. et al.
Tripartite synapses: glia, the unacknowledged partner
Trends Neurosci.
(1999)
BarbeitoL.H. et al.
A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis
Brain Res. Brain Res. Rev.
(2004)
BeglopoulosV. et al.
Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice
J. Biol. Chem.
(2004)
BenvenisteE.N. et al.
Immunological aspects of microglia: relevance to Alzheimer's disease
Neurochem. Int.
(2001)
BiberK. et al.
Neuronal ‘on’ and ‘off’ signals control microglia
Trends Neurosci.
(2007)
BraidaD. et al.
Cognitive function in young and adult IL (interleukin)-6 deficient mice
Behav. Brain Res.
(2004)

BushongE.A. et al.

Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development

Int. J. Dev. Neurosci.

(2004)

ButovskyO. et al.

Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective

Mol. Cell Neurosci.

(2005)

CastellJ.V. et al.

Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes

FEBS Lett.

(1989)

ChenK. et al.

Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide

J. Biol. Chem.

(2006)

ChongY.

Effect of a carboxy-terminal fragment of the Alzheimer's amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells

Life Sci.

(1997)

ChristophersonK.S. et al.

Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis

Cell

(2005)

CombsC.K. et al.

Regulation of β-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha

Neurochem. Int.

(2001)

DabirD.V. et al.

Expression of the small heat-shock protein αB-crystallin in tauopathies with glial pathology

Am. J. Pathol.

(2004)

DanboltN.C.

Glutamate uptake

Progr. Neurobiol.

(2001)

D'AndreaM.R. et al.

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

Neurobiol. Aging

(2004)

DaniJ.W. et al.

Neuronal activity triggers calcium waves in hippocampal astrocyte networks

Neuron

(1992)

DeitmerJ.W. et al.

Calcium signalling in glial cells

Cell. Calc.

(1998)

DermietzelR. et al.

Connexin43 null mice reveal that astrocytes express multiple connexins

Brain Res. Brain Res. Rev.

(2000)

DeWittD.A. et al.

Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease

Exp. Neurol.

(1998)

EikelenboomP. et al.

Inflammatory mechanisms in Alzheimer's disease

Trends Pharmacol. Sci.

(1994)

FellinT. et al.

Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors

Neuron

(2004)

GrammasP. et al.

Inflammatory factors are elevated in brain microvessels in Alzheimer's disease

Neurobiol. Aging

(2001)

HalassaM.M. et al.

The tripartite synapse: roles for gliotransmission in health and disease

Trends Mol. Med.

(2007)

HazellA.S.

Astrocytes are a major target in thiamine deficiency and Wernicke's encephalopathy

Neurochem. Int.

(2009)

AbramovA.Y. et al.

Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity

J. Neurosci.

(2003)

AbramovA.Y. et al.

β-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase

J. Neurosci.

(2004)

AkiguchiI. et al.

Alterations in glia and axons in the brains of Binswanger's disease patients

Stroke

(1997)

AlmerG. et al.

Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis

J. Neurochem.

(1999)

AlmerG. et al.

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis

Ann. Neurol.

(2001)

AloisiF. et al.

Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1-β and tumor-necrosis-factor-α

J. Immunol.

(1992)

AlzheimerA.

Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe

AndriezenW.L.

The neuroglia elements of the brain

Brit. Med. J.

(1893)

AntelJ. et al.

Multiple sclerosis

BachJ.H. et al.

C-terminal fragment of amyloid precursor protein induces astrocytosis

J. Neurochem.

(2001)

BargerS.W. et al.

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature

(1997)

BauerM.K. et al.

Expression and regulation of cyclooxygenase-2 in rat microglia

Eur. J. Biochem.

(1997)

BeersD.R. et al.

Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

Proc. Natl. Acad. Sci. U.S.A.

(2006)

BellR.D. et al.

Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease

Acta Neuropathol.

(2009)

BerglesD.E. et al.

Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus

Nature

(2000)

BerryM. et al.

Cytology and lineage of NG2-positive glia

J. Neurocytol.

(2002)

BezziP. et al.

Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

Nature

(1998)

BezziP. et al.

CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity

Nat. Neurosci.

(2001)

BezziP. et al.

Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate

Nat. Neurosci.

(2004)

BilakM. et al.

PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis

Ann. Neurol.

(2004)

BlaskoI. et al.

TNFα plus IFNγ induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs

FASEB J.

(1999)

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ReviewNeuroglia in neurodegeneration

Abstract

Section snippets

Neuroglia—the concept

Astrocytes organise the brain matter

Neuroglia determines the outcome of neurological pathology

Astrocytes in neurodegeneration and AD

Amyotrophic lateral sclerosis

Concluding remarks

Acknowledgments

Trends Neurosci.

Neuron

Neurobiol. Aging

Prog. Neurobiol.

Trends Neurosci.

Brain Res. Brain Res. Rev.

J. Biol. Chem.

Neurochem. Int.

Trends Neurosci.

Behav. Brain Res.

Int. J. Dev. Neurosci.

Mol. Cell Neurosci.

FEBS Lett.

J. Biol. Chem.

Life Sci.

Cell

Neurochem. Int.

Am. J. Pathol.

Progr. Neurobiol.

Neurobiol. Aging

Neuron

Cell. Calc.

Brain Res. Brain Res. Rev.

Exp. Neurol.

Trends Pharmacol. Sci.

Neuron

Neurobiol. Aging

Trends Mol. Med.

Neurochem. Int.

Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity

J. Neurosci.

β-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase

J. Neurosci.

Alterations in glia and axons in the brains of Binswanger's disease patients

Stroke

Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis

J. Neurochem.

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis

Ann. Neurol.

Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1-β and tumor-necrosis-factor-α

J. Immunol.

Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe

The neuroglia elements of the brain

Brit. Med. J.

Multiple sclerosis

C-terminal fragment of amyloid precursor protein induces astrocytosis

J. Neurochem.

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature

Expression and regulation of cyclooxygenase-2 in rat microglia

Eur. J. Biochem.

Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

Proc. Natl. Acad. Sci. U.S.A.

Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease

Acta Neuropathol.

Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus

Nature

Cytology and lineage of NG2-positive glia

J. Neurocytol.

Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

Nature

CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity

Nat. Neurosci.

Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate

Nat. Neurosci.

PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis

Ann. Neurol.

TNFα plus IFNγ induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs

FASEB J.

Review
Neuroglia in neurodegeneration